Prenatal exposure to valproate has been associated with an elevated risk (10%) for a broad range of congenital malformations including neural tube defects, as well as adverse neurodevelopmental sequelae, including lower IQ and developmental delays in offspring. Several studies have shown that exposure to valproic acid (Depakote) may be associated with increased risk of autism spectrum disorders or autistic traits and/or attentional problems.

A new study examines the association between prenatal exposure to antiepileptic drugs (AEDs) and risk for autism spectrum disorders (ASD) and attention deficit/hyperactivity disorder (ADHD) in the children of women with epilepsy.  In this study, Wiggs and colleagues use data from the Swedish medical register to study risk for ASD and ADHD in a group of 14,614 children born to mothers with epilepsy between 1996 and 2011 and followed up through 2013.  In this cohort, about 23% of the mothers used an anticonvulsant during the first trimester of pregnancy, most commonly carbamazepine (9.7%), lamotrigine (6.8%), and valproic acid (n=699 or 4.8%).  

Children with ASD were identified using ICD-10 diagnoses in the medical record and those with ADHD were identified using ICD-10 diagnoses or the redemption of a prescription for an ADHD medication.

Valproate Exposure Associated with Increased Risk for ASD and ADHD

After adjusting for potential confounding variables, including parental psychiatric history and seizure severity, they observed that the use of valproic acid was associated with a 2.3-fold increased risk for ASD (hazard ratio [HR] 2.30, 95% CI 1.53-3.47) and a 1.7-fold increased risk for ADHD (HR 1.74, 95% CI 1.28-2.38) compared to children whose mothers did not use AEDs.  Use of carbamazepine (n=1,417, 9.7%) was associated with an elevated risk of ASD; however, the risk was substantially attenuated after adjusting for confounders (HR=1.42, 95%CI=1.00-2.02) and further restriction to monotherapy (HR=1.26, 95%CI=0.88-1.79). 

Use of lamotrigine was not associated with risk for ASD (HR=0.66, 95%CI=0.27-1.58) or ADHD (HR=1.00, 95%CI=0.59-1.69). 

The strengths of the study include the fact that this was a large, population-based study with a relatively long follow-up period of up to 17 years.  Given the size of the sample the authors were able to adjust for a large number of potentially confounding risk factors for autism including maternal and paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, and parity. However, limitations of the study include inadequate information about other potentially confounding factors, including perinatal folate supplementation, the use of alcohol or illicit drugs during pregnancy, and possible missed psychiatric diagnoses in the patients.

Findings are Consistent with Previous Studies

The observed increase in risk for ASD in this study was somewhat lower than that observed in a Danish study including 508 children exposed to valproate.  In the Danish cohort, the absolute risk was 4.42% for autism spectrum disorder (adjusted HR, 2.9, 95% CI, 1.7-4.9), and the absolute risk was 2.50% for childhood autism (adjusted HR 5.2, 95% CI, 2.7-10.0). However, when the analysis was restricted only to the 6584 children born to women with epilepsy, the risk for autism spectrum disorder  fell, with and adjusted HR 1.7 (95% CI 0.9-3.2), which is similar to that observed in the current  study.

The fact that the risk for ASD appears to be higher among children born to mothers without epilepsy — presumably most of these women had bipolar disorder — suggests that there may be an interaction between genetic factors and environmental exposures which magnifies the risk for worse neurodevelopmental outcomes.  

Previous studies have also documented an increased risk of ADHD in children exposed to valproate in utero.  Because ADHD is both underdiagnosed and overdiagnosed, it may be difficult to glean accurate data on its prevalence from the medical record.  Furthermore, one could argue that the risk might be underestimated as half of the children were followed only to the age of nine years, and ADHD, particularly milder cases, is often not diagnosed until children are older.    

Avoiding Valproic Acid In Women of Childbearing Age

Multiple studies have documented that prenatal exposure to valproate has been associated with an elevated risk (10%) of a broad range of congenital malformations including neural tube defects, as well as adverse neurodevelopmental sequelae.  Given that 50% of pregnancies are unplanned in the United States, it is questionable if valproic acid can be used safely in women of chilbearing age.

We urge clinicians to adhere to the following recommendations set forth by the European Medical Agency regarding the use of valproic acid in women of childbearing age:

 

Ruta Nonacs, MD PhD

 

Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013: 24;309(16): 1696-703.

Christensen J, Pedersen LH, Sun Y.Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs With Risk for Attention-Deficit/Hyperactivity Disorder in Offspring.  JAMA Netw Open 2019.

Wiggs KK, Rickert ME, Sujan AC, Quinn PD, Larsson H, Lichtenstein P, Oberg AS, D’Onofrio BM.  Antiseizure medication use during pregnancy and risk of ASD and ADHD in children.  Neurology. 2020 Dec 15;95(24):e3232-e3240.